Poster Presentation The International Congress of Neuroendocrinology 2014

Estrogen increases growth of medulloblastoma through estrogen receptor β mediated pro-survival increases in insulin-like growth factor receptor 1 (IGF-1R) signalling (#326)

Scott Belcher 1 , Clifford Cookman 1
  1. University of Cincinnati, Cincinnati, OHIO, United States

Medulloblastoma (MD), the most common pediatric solid tumor, expresses estrogen receptor β (ERβ; ESR2) and 17β‑estradiol (E2) increases proliferation of MD-derived cells through activation of ERβ in vitro. Reported here are results from in vitro and in vivo studies demonstrating the effect of E2 on apoptosis and defining the underlying mechanism. Human MD-derived D283Med cells were fully protected from metabolic stress induced apoptosis by E2 and the ERβ agonist DPN. Neither the ERα agonist PPT nor the GPR30 agonist G-1 mimicked the effect of E2 or DPN. The pro-survival effect of E2 was blocked by non-selective (ICI 182,780) and ERβ-selective (PHTPP) ER antagonists, but not the ERα antagonist MPP. Experiments were also conducted to determine whether the ERβ-dependent protective effects of E2 involved growth factor signaling. Inhibition of either IGF-1R or MEK 1/2 activity blocked the protective effect of E2 in D283Med cells. Those data demonstrated the dependence of the E2/ERβ protective effects on activation of IGF-1/ERK signaling. The role of ER signaling in MD growth was investigated in the Ptch+/- P53-/- MD model and a novel PtchC/C Atoh1-cre mouse model of MD in which ERβ was also knocked out. Medulloblastoma growth rate were inhibited and tumor mass was decreased by anti-estrogen treatment and ERβ-loss of function. Anti-estrogen treatment also induced increased apoptosis, decreased IGF-1R expression, and decreased active ERK1/2. Those in vivo data are in complete agreement with the in vitro data and demonstrate that ERβ activation in MD stimulates pro-survival signaling that resulted in increased MD tumor growth.